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FABAD J. Pharm. Sci., 45, 2, 117-124, 2020

RESEARCH ARTICLE The Role of Amphotericin B Alone and in Combination with Different and on Biofilms Produced by Species

Mayram HACIOGLU*° , Ozlem OYARDI** , Berna OZBEK-CELIK***

The Role of Amphotericin B Alone and in Combination with Amfoterisin B’nin Tek Başına ve Çeşitli Antibiyotik ve Different Antibiotics and Antifungals on Biofilms Produced Antifungallerle Birlikte Candida Biyofilmleri Üzerine Etkisi by Candida Species

SUMMARY ÖZ

Biofilm formation by Candida species is highly resistant to commonly Biyofilm oluşumu Candida türlerinde antifungallere daha dirençli used agents and is difficult to treat. Therefore, this study olmalarını sağladığından tedavisi güç enfeksiyonlara neden focused on effectiveness of combination therapy against Candida olmaktadır. Bu amaçla, bu çalışmada Candida biyofilmlerine biofilms. The antimicrobial activities of amphotericin B (1 µg/ karşı kombinasyon tedavisinin etkinliği araştırılmıştır. ml or 10 µg/ml) alone or in combination with various antibiotics Amfoterisin B’nin (1 µg / ml veya 10 µg / ml) tek başına veya ( (20 µg/ml), tigecycline (20 µg/ml), (30 µg/ml), çeşitli antibiyotiklerle [(doksisiklin (20 µg / ml), tigesiklin (20 µg / (120 µg/ml), ciprofloxacin (20 µg/ml)) or antifungals ml), kolistin (30 µg / ml), rifampisin (120 μg / ml), siprofloksasin ( (2.5 µg/ml), (10 µg/ml), (20 μg / ml)] veya çeşitli antifungaller [(klotrimazol (2.5 μg / ml), (10 µg/ml), (2.5 µg/ml) and (10 µg/ml)) anidulafungin (10 μg / ml), kaspofungin (10 μg / ml), itrakonazol were investigated against fungal biofilms produced by C. albicans (2.5 μg / ml), flukonazol (10 µg/ml)] ile kombinasyonlarının SC5314, C. tropicalis ATCC 750 and C. parapsilosis ATCC C. albicans SC5314, C. tropicalis ATCC 750 ve C. parapsilosis 22019. Fungal viability was monitored by culture (colony-forming ATCC 22019 tarafından üretilen biyofilmlere karşı etkinlikleri unit (CFU). According to the results, rifampicin and ciprofloxacin araştırılmıştır. Sonuçlarımız rifampisin ve siprofloksasinin, enhanced the activity of amphotericin B (10 µg/ml). Among the amfoterisin B’nin (10 μg / ml) aktivitesini arttırdığını, antifungals, clotrimazole displayed the most significant effect in antifungaller arasında ise klotrimazol ve amfoterisin B (10 μg combination with amphotericin B (10 µg/ml), especially against C. / ml) kombinasyonunun özellikle C. parapsilosis biyofilmlerine parapsilosis biofilms. karşı etkili olduğunu göstermiştir. Sonuç olarak, amfoterisin B Consequently, combinations of amphotericin B and or ve antibiyotik veya antifungal kombinasyonları Candida spp. antifungal could be a promising option for the treatment of Candida biyofilmlerinin tedavisi için ümit verici bir seçenek olabileceği biofilms. düşünülmüştür.

Key Words: Candida, Biofilm, Amphotericin B, Clotrimazole, Anahtar Kelimeler: Candida, Biyofilm, Amfoterisin Antifungal combinations, Antibiotics combinations. B, Klotrimazol, Antifungal kombinasyonu, Antibiyotik kombinasyonu.

Received: 18.07.2019 Revised: 12.11.2019 Accepted: 25.12.2019

* ORCID: 0000-0003-0823-631X Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Istanbul University, Beyazit, Istanbul, ** ORCID: 0000-0001-9992-7225 Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Istanbul University, Beyazit, Istanbul, *** ORCID: 0000-0001-8909-8398 Department of Pharmaceutical Microbiology, Faculty of Pharmacy, Istanbul University, Beyazit, Istanbul,

° Corresponding Author; Mayram HACIOGLU Phone: + 90 212 440 00 00 /13522, E-mail: [email protected] 117 Hacioğlu, Oyardi, Özbek-Çelik

INTRODUCTION are required to combat biofilm-related Candida in- Candida species are opportunistic pathogens that fections (Taff et al., 2013). The aim of this study was reside in the human oral cavity, vagina, and gastro- to evaluate the in vitro effects of antibacterial agents intestinal tract natural microbiota (Cho et al., 2014; and traditional antifungals, both alone and in combi- nation with amphotericin B against mature biofilms Kumamoto, 2011). caused by Candida produced by C. albicans SC5314, C. tropicalis ATCC species range from superficial infections to invasive 750 and C. parapsilosis ATCC 22019. infections including and endocarditis, that frequently occur in immunocompromised and MATERIALS AND METHODS hospitalized patients. Drug abuse, organ transplanta- Strains and growth conditions tion, surgery, burns, and malignancies are major risk The three most common biofilm-forming Can- factors for invasive Candida infections and thus affect dida species, reference isolates C. albicans SC5314 morbidity and mortality rates. is (ATCC MYA-2876), C. tropicalis ATCC 750 and C. identified as the predominant pathogen in ATCC 22019 were used in this study. All species infections. Nevertheless, recently non-Candi- three isolates are susceptible to the antifungals used da albicans Candida (NCAC) species, such as C. trop- in this study. Isolates were sub-cultured from frozen icalis and C. parapsilosis, are increasing in prevalence stocks onto Sabouraud dextrose agar (SDA, Difco, (Diba et al., 2018; Fesharaki et al., 2013; Yesilkaya et Sparks, MD, USA) plates and incubated at 30°C over- al., 2017). night to generate cultures for use in the following ex- Candida species biofilms are virulence factors periments. Yeast extract peptone dextrose (YPD, Sig- that promote especially when the host de- ma-Aldrich, St. Louis, MO, USA) agar and broth, and fense system is impaired during treatment. Microor- Roswell Park Memorial Institute (RPMI, Sigma-Al- ganisms form biofilms as a survival strategy. Biofilm drich, St. Louis, MO, USA) medium, supplemented embedded microorganisms possess resistance to both with L-glutamine and buffered with morpholinepro- antimicrobial agents and host immune responses panesulfonic acid (MOPS; Sigma-Aldrich, St. Louis, when compared to their planktonic forms. Antimi- MO, USA), was used in the biofilm assays. crobial resistance is mainly due to low penetration Antimicrobial agents of antibiotics into biofilm matrix, low oxygen and nutrient concentrations, and expression of biofilm Amphotericin B deoxycholate (purity; 99,8%, specific genes (Taff et al., 2013). Candida species can Bristol-Myers Squibb, New York, USA), clotrimazole cause life-threatening problems by forming biofilms (purity; 99,97 %, Bristol-Myers Squibb, New York, on the surfaces of medical devices such as implants, USA), fluconazole (purity; 99,8%, Pfizer, New York, heart valves, catheters, and ocular lenses (Kojic and USA), anidulafungin (purity; 98,8%, Pfizer, New Darouiche, 2004). Moreover, Candida biofilms pose York, USA), caspofungin (purity; 100%, Merck Sharp Dohme, Kenilworth, NJ, USA), itraconazole (purity; a significant risk in cystic fibrosis (Chotirmall et al., 100%, Sigma Aldrich, St. Louis, MO, USA), doxycy- 2010; Williams et al., 2016). Previous studies have cline (purity; 98,9 %, Kocak Pharma Ilac, Turkey), shown that 60-70% of the Candida isolates from dif- tigecycline (purity; 99,7%, Wyeth Pharmaceuticals, ferent clinical materials produce biofilm (Tellapraga- Madison, NJ, USA), colistin (purity; 100%, Sigma da et al., 2014). Aldrich, St. Louis, MO, USA), rifampicin (purity; The absence of appropriate antifungal therapy is a 99,99%, Kocak Pharma Ilac, Turkey) and ciprofloxa- major contributor to the increasing mortality, as well cin (purity; 99,99%, Kocak Pharma Ilac, Turkey) were as hospital length of stay and cost of the treatment, in obtain from the manufacturers. Stock solutions were Candida infections. One of the most preferred anti- prepared at 1280 mg/L for the antifungals and 5120 fungal agents in the clinical practice is amphotericin mg/L for the antibiotics, according to Clinical and B. Amphotericin B is a polyene class antifungal that Laboratory Standards Institute (CLSI) (CLSI, 2006; acts by binding to in the . CLSI 2012; CLSI 2014) and stored at -80°C for up to Susceptibility studies indicate that Candida biofilms 6 months. The final concentrations of antimicrobial may be up to 1000-times more resistant than plank- agents used for biofilm assay were their peak serum tonic cells to antimicrobial agents (Tobudic et al., concentration (Cmax) values after intravenous drug 2012), resulting in potentially high toxicity to host administration. Antifungal agents’ susceptibility was cells (Mazu et al., 2016). Therefore, new drug strat- performed by broth dilution according to CLSI rec- egies, therapies and synergistic drug combinations ommendations. All strains were determined as sus- 118 FABAD J. Pharm. Sci., 45, 2, 117-124, 2020

ceptible to anidulafungin (≤2 µg/ml), caspofungin (≤2 (900 rpm) and sonication (both 5 min) (Meddison). µg/ml), itraconazole (<0.125 µg/ml) and fluconazole The well contents were collected into sterile tubes and (<8 µg/ml). C. parapsilosis ATCC 22019 was used as vortexed and sonicated again after the addition of 200 the susceptibility test control strain (CLSI, 2012). µl PBS. To enumerate the pathogen load cultures were Biofilm formation serially diluted in sterile PBS and plated onto SDA us- ing the drop plate method. Plates were incubated at Biofilms were formed in microtiter plates wells 37 °C for 24 h and colonies counted and expressed as as previously described by Ramage et al. (2001) [18]. CFU (Tavernier et al., 2017). Briefly, YPD broth cultures were inoculated directly from overnight YPD agar cultures, and cultured for a Statistical analysis further 24 h, in an orbital shaker at 30˚C. YPD broth All experiments were performed in triplicate in cultures were centrifuged (about 3,000 rpm, 5-10 two separate sets of experiments. All data are ex- min) and the pellet washed twice with sterile physio- pressed as mean values with corresponding standard logical buffered (PBS), followed by resuspend- deviations. One-way ANOVA and Bonferroni’s Mul- ing in RPMI 1640 to a cellular density equivalent to tiple Comparison tests were used to compare the dif- 1x106 cells ml-1. Biofilms were formed by adding 200 ferences between biofilms and a p-value of <0.05 was µl of the standardized cell suspension into selected considered statistically significant. polystyrene flat-bottomed 96-well tissue culture mi- RESULTS crotiter plates wells (Greiner Bio-One, Kremsmuen- ster, Austria) and incubated for 48 h at 37˚C. After Amphotericin B and antibiotic combinations incubation, the supernatant was gently aspirated, and against Candida spp. biofilms the non-adherent cells removed by washing the bio- The antimicrobial effects of amphotericin B at films three times with PBS (Ramage et al., 2001). two different concentrations (1 µg/ml or 10 µg/ml) Biofilm CFU assay alone and combination with antibiotics were evaluat- ed. We observed that 10 µg/ml amphotericin B and After obtaining the biofilms, wells were treated ciprofloxacin combinations had better antimicrobial with antimicrobials at their Cmax values (doxycy- activity against C. albicans and C. tropicalis biofilms cline (20 µg/ml), tigecycline (20 µg/ml), colistin (30 (p<0.05) than other combinations (Figure 1 a, c). In µg/ml), rifampicin (120 µg/ml), ciprofloxacin (20 µg/ addition, the combination of amphotericin B (10 µg/ ml), clotrimazole (2,5 µg/ml), anidulafungin (10 µg/ ml) and rifampicin was the most effective in reducing ml), caspofungin (10 µg/ml), itraconazole (2,5 µg/ml) C. parapsilosis biofilms viability (Figure 1 b). Further- and fluconazole (10 µg/ml)). In addition, amphoteri- more, amphotericin B (10 µg/ml) with all antibiotic cin B was tested at 1 µg/ml or 10 µg/ml due to interpa- combinations displayed greater than one log reduc- tient variabilities of amphotericin B Cmax and areas tion for each combination against C. tropicalis bio- under concentration-time curves (AUC) that were films (Figure 1 c). 8- to 10-fold greater for patients treated with liposo- mal amphotericin B than for patients treated with am- Amphotericin B and antifungal combinations photericin B deoxycholate (Heinemann et al., 1997). against Candida spp. biofilms Twofold concentration of tested antimicrobials Cmax The antibiofilm activities of amphotericin B alone values were prepared in RPMI. In wells containing and in combination with antifungals against Candida combinations of amphotericin B and antimicrobi- spp. was also evaluated at two different concentrations als, 100 µl of each antimicrobial was placed directly (1 µg/ml or 10 µg/ml). The most remarkable result was onto the biofilm. In wells containing antimicrobials that clotrimazole was the most effective antifungal in alone, 100 µl of RPMI was added together with the combination with amphotericin B (10 µg/ml) against antimicrobial to provide equivalent volumes added to C. tropicalis and C. parapsilosis biofilms (Figure 2 b, the biofilms. Control wells contained no antimicro- c). Furthermore, clotrimazole and caspofungin alone bial agents. The biofilm cultures were incubated for were the most effective antifungals against Candida an additional 24 h (Ramage et al., 2001). After 24 h of biofilms. However, there was no significant reduction antimicrobial exposure, the biofilms were rinsed with in C. albicans biofilms with any of the antifungals or 200 µl PBS, and the biofilms detached by vortexing combinations studied (Figure 2 a).

119 Hacioğlu, Oyardi, Özbek-Çelik

CNT: Control, AMP: Amphotericin B, DOX: Doxycycline, TGC: CNT: Control, AMP: Amphotericin B, CLT: Clotrimazole, ANI: Tigecycline, COL: Colistin, RIF: Rifampicin, CIP: Ciprofloxacin Anidulafungin, CSP: Caspofungin, ITR: Itraconazole, FLU: Flu- conazole Figure 1. Amphotericin B and antibiotic combina- Figure 2. Amphotericin B and antifungal combina- tions against Candida spp. biofilms. Average number tions against Candida spp. biofilms. Average number of cfu of the microorganisms’ recovered from bio- of cfu of the microorganisms’ recovered from bio- films were shown films were shown a) C. albicans biofilms a) C. albicans biofilms b) C. parapsilosis biofilms b) C. parapsilosis biofilms c) C. tropicalis biofilms c) C. tropicalis biofilms 120 FABAD J. Pharm. Sci., 45, 2, 117-124, 2020

DISCUSSION bacterial RNA polymerase, was previously identified In recent years, C. albicans and NCAC infections (Del et al., 2011). Ciprofloxacin, that affects bacteri- have been steadily increasing particularly in the pa- al DNA gyrase, was previously demonstrated to in- tients with risk factors such as immunosuppression or teract pharmacodynamically with antifungal agents drug abuse (Diba et al., 2018; Fakhim et al., 2017b, by altering their fungal growth-inhibitory activities, Fesharaki et al., 2013; Lamoth et al., 2018; Yesilkaya et similar to rifampicin (Stergiopoulou et al., 2011). Fur- al., 2017). Also, most likely due to the over prescrip- thermore, Stergiopoulou et al. (2008) has shown that tion of antifungals, an important shift in infection rate low dose ciprofloxacin may increase pore formation with C. albicans to NCAC has occurred. The emer- induced by amphotericin B on fungi cell wall, thus gence of new multidrug-resistant NCAC strains such lead synergistic effect. In this study the most effective as C. auris become a significant threat worldwide combination against C. parapsilosis biofilm was am- (Fakhim et al., 2017a; Lamoth et al., 2018). Ampho- photericin B and rifampicin. The enhanced antifungal tericin B, fluconazole and are most activity observed with the combination of amphoteri- commonly prescribed in fungal infections (Lamoth et cin B, ciprofloxacin and rifampicin, may be explained al., 2018). However, since Candida species are resis- by more effective fungal cell penetration. tant to antifungals, studies to identify alternate treat- Previous studies have demonstrated that colistin ment options such as combinational therapies, has alone affected the antifungal cell membrane at high gained significance (Fakhim et al., 2017a, Fakhim et concentrations (Schwartz et al., 1972). Colistin may al., 2017b). have increased antifungal efficacy if given at lower According to a physiologically based pharmacoki- concentration in combination with amphotericin B netic model, plasma concentrations of drugs can vary (TeixeirSantos et al., 2016). However, there is no study with time due to different rates of absorption, distri- evaluating efficacy of this combination on Candida bution, metabolism and excretion (ADME) (Zhao et biofilms. Several studies evaluating doxycycline and al., 2011). Pharmacokinetic drug interaction profiles tigecycline antifungal effectivity against C. albicans are important to assess in vivo, as well as pharmacoki- biofilms have indicated that addition of amphotericin netic parameters such as Cmax and AUC when drug B increased antifungal activity of these drugs (Hacio- combinations are applied in clinical cases. Based on glu et al., 2018; Miceli et al., 2009). However, these the clinical importance of these parameters, the aver- studies were performed with high concentrations of age plasma concentrations were used to assist in un- antibiotics. The novelty of our study was to use plas- derstanding these interactions in this study. ma concentrations, not toxic levels of antibiotics. We observed that colistin, tigecycline and doxycycline The polyene antifungal agent amphotericin B, is had significant effects especially on C. tropicalis bio- the most reliable and broad-spectrum therapeutic films, even at lower plasma concentrations. agent for invasive fungal infections, including can- didiasis and biofilm infections (Hamill, 2013; Tour- According to a study investigated amphotericin il et al., 2018). Since, yeasts are much more resistant B (1 µg/ml) and caspafungin combination, there was to antifungal drugs in biofilms, high, frequently host no synergistic interactions against C. albicans biofilm cell toxic concentrations of amphotericin B are need- (Tobudic et al., 2010). Similarly, amphotericin B-flu- ed to destroy Candida biofilms or to decrease the conazole and amphotericin B-caspafungin combina- cell number (Laniado-Laborin and Cabrales-Vargas, tions against C. albicans biofilm have been determined 2009). In order to avoid side effects and toxicities of as indifferent (Bachmann et al., 2003). In this study, amphotericin B, different strategies have been devel- amphotericin B and antifungal combinations except oped, including various drug formulations, combi- clotrimazol have not shown any significant result. An national therapies (Aversa et al., 2017; Spader et al., antifungal clotrimazole, which is widely used 2019; Touril et al., 2018). Therefore, in this study we as a topical treatment for candidiasis, has become an combined representative antifungal and antibacterial area of intense research for the treatment of invasive agents with amphotericin B to determine the effect of fungal infections in select, high-risk patient popula- combinations on Candida biofilms. tions (Crowley and Gallagher, 2014). Interestingly our results showed that clotrimazole displayed antifungal According to the results, amphotericin B and an- activity similar to caspofungin against NCAC, both tibiotic combinations demonstrated that rifampicin alone and in combination with amphotericin B. To and ciprofloxacin can enhance the activity of ampho- our knowledge this is the first report of clotrimazole tericin B against Candida biofilms. The activity of ri- having antibiofilm activity against NCAC biofilms. fampicin against fungal RNA polymerase, as well as 121 Hacioğlu, Oyardi, Özbek-Çelik

Since microbial biofilms are highly resistant to an- Clinical and Laboratory Standards Institute (CLSI). timicrobials, even a 1-log reduction in the number of (2006). Methods for dilution antimicrobial suscepti- microorganisms is very important in therapy. Conse- bility tests for that grow aerobically. Approved quently, it was determined that nucleic acid inhibiting Standard M7-A7. 7th ed. Wayne: CLSI. antibacterial compounds enhance amphotericin B’s Clinical and Laboratory Standards Institute (CLSI). antibiofilm activity at plasma concentrations. In ad- (2012). Reference method for broth dilution antifun- dition, clotrimazole, an antifungal agent, gal susceptibility testing of yeasts. In: fourth informa- destroyed biofilms more effectively than an- tional supplement M27-S4. Wayne: CLSI. tifungals, fluconazole and itraconazole. As expected, an echinocandine antifungal caspofungin alone was Clinical and Laboratory Standards Institute (CLSI). more effective on Candida biofilms than other anti- (2014). Performance and standards for antimicrobial fungals. In conclusion, selected drug combinations susceptibility testing. In: twenty-second information- could be potential alternatives for the current thera- al supplement M100-S24. Wayne: CLSI. peutic management of fungal infections, but to date Crowley, P. D., & Gallagher, H. C. (2014). Clotrima- remain in the laboratory experimental phase. Further zole as a pharmaceutical: past, present and future. combinations need to be tested to confirm the poten- Journal of Applied Microbiology, 117(3), 611-617. tial synergistic effects between these antibiotics and https://doi.org/10.1111/jam.12554 antifungals at different concentrations. Del Pozo, J. L., Francés, M. L., Hernáez, S., Serrera, ACKNOWLEDGEMENTS A., Alonso, M., & Rubio, M. F. (2011). Effect of This research did not receive any specific grant amphotericin B alone or in combination with ri- from funding agencies in the public, commercial, or fampicin or clarithromycin against Candida spe- not-for-profit sectors. cies biofilms. The International Journal of Artificial Organs,, 34(9), 766-770. https://doi.org/10.5301/ CONFLICT OF INTEREST ijao.5000023 The authors declare no conflict of interest, Diba, K., Makhdoomi, K., Nasri, E., Vaezi, A., Javid- finan-cial or otherwise. nia, J., Gharabagh, D. J., ... & Fakhim, H. (2018). REFERENCES Emerging Candida species isolated from renal trans- Aversa, F., Busca, A., Candoni, A., Cesaro, S., Gir- plant recipients: species distribution and suscepti- menia, C., Luppi, M., ... & Venditti, A. (2017). bility profiles. Microbial Pathogenesis, 125, 240-245. Liposomal amphotericin B (AmBisome®) at be- https://doi.org/10.1016/j.micpath.2018.09.026 ginning of its third decade of clinical use. Jour- Fakhim, H., Chowdhary, A., Prakash, A., Vaezi, A., nal of Chemotherapy, 29(3), 131-143. doi: Dannaoui, E., Meis, J. F., & Badali, H. (2017). In 10.1080/1120009X.2017.1306183 vitro interactions of echinocandins with Bachmann, S. P., Ramage, G., VandeWalle, K., Pat- against multidrug-resistant Candida auris. Antimi- terson, T. F., Wickes, B. L., & López-Ribot, J. L. crobial Agents and Chemotherapy, 61(11), e01056- (2003). Antifungal combinations against Candida 17. doi: 10.1128/AAC.01056-17 albicans biofilms in vitro. Antimicrobial Agents and Fakhim, H., Emami, S., Vaezi, A., Hashemi, S. M., Fa- Chemotherapy, 47(11), 3657-3659. doi: 10.1128/ eli, L., Diba, K., ... & Badali, H. (2017). In vitro AAC.47.11.3657–3659.2003 activities of novel azole compounds ATTAF-1 and ATTAF-2 against fluconazole-susceptible and-re- Cho, T., Nagao, J. I., Imayoshi, R., & Tanaka, Y. (2014). sistant isolates of Candida species. Antimicrobial Importance of diversity in the oral microbiota in- Agents and Chemotherapy, 61(1), e01106-16. doi: cluding Candida species revealed by high-through- 10.1128/AAC.01106-16 put technologies. International Journal of Dentistry, 2014, 1-5. http://dx.doi.org/10.1155/2014/454391 Fesharaki, S. H., Haghani, I., Mousavi, B., Kargar, M. L., Boroumand, M., Anvari, M. S., ... & Badali, H. Chotirmall, S. H., Greene, C. M., & McElvaney, N. (2013). Endocarditis due to a co-infection of Can- G. (2010). Candida species in cystic fibrosis: a road dida albicans and in a drug abus- less travelled. Sabouraudia, 48(Supplement_1), er. Journal of Medical Microbiology, 62(11), 1763- S114-S124. https://doi.org/10.3109/13693786.20 1767. https://doi.org/10.1099/jmm.0.060954-0 10.503320

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